Abstract

BackgroundColorectal cancer (CRC) arises as a consequence of genetic events such as gene mutation and epigenetic alteration. The aim of this study was to identify new hypermethylated candidate genes and methylation-based therapeutic targets using vincristine in CRC.MethodsWe analyzed the methylation status of 27,578 CpG sites spanning more than 14,000 genes in CRC tissues compared with adjacent normal tissues and normal colon tissues using Illumina bead chip array. Twenty-one hypermethylated genes and 18 CpG island methylator phenotype markers were selected as candidate genes. The methylation status of 39 genes was validated by quantitative methylation-specific polymerase chain reaction in CRC tissues, adjacent normal tissues, normal colon cells, and three CRC cell lines. Of these, 29 hypermethylated candidate genes were investigated using the demethylating effects of 5-aza-2′-deoxycytidine (5-aza-dC) and vincristine in CRC cells.ResultsThirty-two out of 39 genes were hypermethylated in CRC tissues compared with adjacent normal tissues. Vincristine induced demethylation of methylated genes in CRC cells to the same extent as 5-aza-dC. The mRNA expression of AKR1B1, CHST10, ELOVL4, FLI1, SOX5, STK33, and ZNF304 was restored by treatment with 5-aza-dC and vincristine.ConclusionThese results suggest that these novel hypermethylated genes AKR1B1, CHST10, ELOVL4, SOX5, STK33, and ZNF304 may be potential methylation biomarkers and therapeutic targets of vincristine in CRC.

Highlights

  • Colorectal cancer (CRC) arises as a consequence of genetic events such as gene mutation and epigenetic alteration

  • We found a total of 3,177 CpG sites in the promoter regions (1,704 CpG sites, 53.6%) and non-promoter regions (1,473 CpG sites, 46.4%), with aberrant methylated CpG sites identified in CRC tissues compared with adjacent normal and normal colon tissues, according to statistical significance determined by the paired t-test and an false discovery rate (FDR) P value of

  • We selected 21 candidate genes that contained strongly hypermethylated CpG sites in promoter CpG islands in CRC tissues compared with adjacent normal tissues (Figure 1)

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Summary

Introduction

Colorectal cancer (CRC) arises as a consequence of genetic events such as gene mutation and epigenetic alteration. CRC is a consequence of genetic events including gene mutations and epigenetic alterations that transform colonic epithelial cells into adenocarcinoma cells [1]. Gene-specific methylation changes in promoter CpG regions have been largely related to biological processes of tumor progression including cell proliferation, communication, adhesion, mobility, signal transduction, and drug resistance [7]. Aberrant methylation of CpG islands in the promoter or exon 1 regions of tumor suppressor genes has been correlated with transcriptional silencing of downstream genes in colorectal cancer [8,9]. There are many lines of evidence that have been proposed as potential biomarkers for CRC in humans, many researchers continue to research new CRC-specific methylation markers. QMSP is a sensitive tool and offers quantitative analysis of DNA methylation status [25]

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